The Paediatric EVICEL® Neuro Study
Research type
Research Study
Full title
A Prospective Randomized Controlled Study Evaluating the Safety and Efficacy of EVICEL® used for Suture-Line Sealing in Dura-Mater Closure during Paediatric Neurosurgical Cranial Procedures
IRAS ID
153733
Contact name
Benedetta Pettorini
Contact email
Sponsor organisation
ETHICON
Eudract number
2013-003558-26
Research summary
Research Summary
his is a prospective randomized, open-label, multi-center controlled study evaluating the effectiveness of EVICEL® and sutures compared to additional sutures only to obtain an intraoperative watertight dural closure.
Paediatric subjects, undergoing elective or urgent craniotomy/craniectomy for
pathological processes in the posterior fossa (such as benign or malignant tumors,
vascular malformations, and Chiari 1 malformations) or in the supratentorial region
and who were demonstrated to have persistent cerebrospinal fluid (CSF) leakage
following a primary attempt at suture closure of the dural incision.Paediatric subjects for this study are classified as:
Newborn infants (birth to 27 days. Pre-term newborn infants born = 37 weeks
gestation will be included within the group); Infants and toddlers (28 days to <24 months); Children (2 to 11 years); Adolescents (12 to <18 years)42 children with intra-operative cerebrospinal fluid (CSF) leak following primary suturing of the dura will be randomized in a 2:1 (Evicel and sutures:Additional Sutures) allocation ratio.
Subjects will be followed post-operatively through discharge and for 30 days post-surgery. The incidence of CSF leaks will be assessed within 5 days and 30 days post-operatively.
Summary of Results
Analysis Sets
A total of 40 subjects recruited at 7 centers in the UK were randomized into this study, with 25 subjects in the EVICEL group and 15 subjects in the Sutures group. All subjects completed the study as planned.
A total of 102 protocol deviations were reported in 19/26 subjects (73.1%) treated with EVICEL and 13/14 subjects (92.9%) treated with Sutures alone. Nine (9) of these 102 protocol deviations were assessed as major protocol deviations; these affected 4 subjects in the EVICEL group and 5 subjects in the Sutures group.
The FAS (ITT set) consisted of 25 subjects (100.0%) randomized to EVICEL and 15 subjects (100.0%) randomized to Sutures. In the FAS, the Sutures group consisted of 14 subjects treated with Sutures alone and 1 subject (22202) that was randomized to Sutures but received EVICEL. This subject was analyzed in the Sutures group for ITT set and in the EVICEL group for the Safety set. Therefore, the Safety set consisted of 26 EVICEL subjects and 14 Sutures subjects. The PP set consisted of 22 EVICEL subjects (88.0%) and 10 subjects (66.7%) randomized to Sutures.
Demographics
The study population had a mean (standard deviation [sd]) age of 9.7 (4.4) years in EVICEL group and 9.2 (4.3) years in Sutures group, and consisted of more males in the EVICEL group (56.0%) than in Sutures group (60.0%). Subjects included in the study ranged from 7 months to 17 years of age, with a median of 10 years in both groups. Comorbidities were most frequently reported in the following system organ classes: Neoplasms (benign or malignant) and unspecified (including cysts and polyps) (67.5%); Nervous system disorders (65.0%); Congenital, familial, and genetic disorders (32.5%); Immune system disorders, Infections and infestations, and Cardiac disorders (all 10.0%); and Respiratory, thoracic, and mediastinal disorders, Musculoskeletal and connective tissue disorders, and Investigations (all 7.5%). Overall, 30% of subjects had previous surgery, no subject had a history of superficial vein thrombosis (SVT) or deep vein thrombosis/pulmonary embolism (DVT/PE), and no subject had a family history of DVT/PE. Overall, 22.5% had never smoked, while, for 70.0%, this was not relevant due to patient age.
Surgical Indication and Approach
Overall, the most common indication for surgery was tumor (65.0%), followed by epilepsy (17.5%), arteriovenous (A-V) malformation (7.5%), “other” conditions (5.0%), arachnoid cyst 2.5%, and Chiari malformation (2.5%). In the total group, as well as in the EVICEL and Suture groups, the most frequent surgical procedure was craniotomy, and the most common type of approach was the supratentorial. Overall, 97.5% of subjects underwent a craniotomy and 2.5% underwent a craniectomy. Supratentorial approach was used in 82.5% of the subjects, and a posterior fossa approach was used in 17.5%.
The distribution of the operative procedure and the type of approach was similar in the two treatment groups: 96.0% of subjects in the EVICEL group and 100.0% subjects in the Sutures group underwent craniotomy, while 84.0% of the subjects in EVICEL group and 80.0% of the subjects in Sutures group underwent a supratentorial approach.
Operative Parameters
As per protocol, all subjects had a documented CSF leak prior to randomization. Overall, 24 subjects (60.0%) had spontaneous CSF leak, whereas in 15 subjects (93.8%) a CSF leak was detected after performing a Valsalva maneuver. In the EVICEL group, 14 subjects (56.0%) had a spontaneous CSF leak and, of the 11 subjects with no spontaneous CSF leak and in whom a Valsalva maneuver was performed, 11 subjects (100.0%) had a CSF leak after the Valsalva maneuver. In the Sutures group, 10 subjects (66.7%) had a spontaneous CSF leak and, of the 5 subjects with no spontaneous CSF leak, 4 subjects (80.0%) had a CSF leak after the Valsalva maneuver was performed.
The operative parameters relating to the duration of surgery and hospitalization were similar in the 2 treatment groups. The median duration of surgery and median time in operating room were 305 minutes and 376 minutes, respectively, for EVICEL, and 288 minutes and 361 minutes, respectively, for Sutures. The median total number of nights in hospital and the median number of post-op nights in hospital was 6 and 5, respectively, for EVICEL, and 7 and 7, respectively, for Sutures.
In twenty-three of the twenty-five subjects in the EVICEL treatment group (92.0%), 1 EVICEL kit was used, while in two subjects (8.0%), a second EVICEL kit was used. The median amount of EVICEL used in the subjects was 4.0 mL (range 2.0-8.0 mL). For the 14 subjects who received sutures, the median number of sutures used was 2.0 (1.0, 12.0).
Efficacy
EVICEL was shown to be effective for suture-line sealing in dura-mater closure to obtain intra-operative watertight closure in paediatric patients undergoing elective or urgent cranial neurosurgery. The primary endpoint was the proportion of success (intra-operative watertight closure) in the treatment of intra-operative CSF leakage defined as no CSF leakage from the sutured dural repair intra-operatively, during Valsalva maneuver at 20-25 cm H2O pressure for 5-10 seconds.
The primary effectiveness analysis was based on the full analysis set. Overall, in the FAS, 23 of 25 EVICEL subjects, and 5 of 15 Suture subjects were considered a success, constituting success rates of 92.0% for EVICEL and 33.3% for Sutures. Two (2) subjects in the EVICEL group and 10 subjects in the Sutures group were considered failures. The proportion of subjects with primary endpoint successes was higher in EVICEL group (92.0%) compared with Sutures group (33.3%); the ratio of proportions (EVICEL/Sutures) was 2.76 (95% CI: 1.53-6.16). Within the posterior fossa stratum, 2/4 EVICEL subjects and 0/3 Sutures subjects were considered a success, constituting success rates of 50.0% and 0.0%, respectively. Within the supratentorial stratum, 21/21 EVICEL subjects and 5/12 Sutures subjects were considered a success, constituting success rates of 100.0% for EVICEL and 41.7% for Sutures.
The supportive analysis (PP set) shows similar results in EVICEL group, with a success rate of 90.9% (20 of 22 subjects), and higher success rate for Sutures group (40.0% [4 of 10 subjects]). The ratio of proportions (EVICEL/Sutures) was 2.27 (95% CI: 1.27-5.53). The primary effectiveness endpoint was also analyzed using the Safety set. Overall, 23 of 26 subjects (88.5%) in the EVICEL group and 5 of 14 subjects (35.7%) in the Sutures group were considered successes.
Analyses of intra-operative parameters (FAS) showed that, in the EVICEL group, most subjects (92.0%) were treated with 1 application of EVICEL. The majority of subjects received 1 layer of EVICEL, and most of the subjects had no CSF leak following EVICEL application and the final Valsalva maneuver. For the first EVICEL application, 18 subjects (72.0%) received 1 layer and 7 subjects (28.0%) received 2 layers of EVICEL. A spontaneous leak after EVICEL application was observed in 1 subject (4.0%). A second EVICEL application was documented in 2 subjects (8.0%). For the second EVICEL application, 1 subject (50.0%) received 1 layer and 1 subject (50.0%) received 2 layers. A spontaneous CSF leak was observed in 1 subject (50.0%) after the second application.
The most frequently used method of application for EVICEL was via dripping. For EVICEL, a 4 cm control tip was used in 64.0% of the subjects for the first application. A 6 cm yellow flexible tip was used in 32.0% of subjects for the first application and in both of the 2 subjects (100.0%) for the second application.
Following treatment, watertight closure was obtained for 23 of 25 subjects in the EVICEL group (92.0%), and 5 of 15 subjects in the Sutures group (33.3%); 2 EVICEL subjects and 10 Suture subjects did not have watertight closure after treatment. Of the 10 subjects in the Sutures group that did not have watertight closure, 1 subject (22202) was randomized to receive Sutures but instead received EVICEL.
Overall, rescue therapy was administered to 12 subjects (30.0%), from which 2 subjects were in the EVICEL group (8.0%) and 10 subjects were in the Sutures group (66.7%). These 12 subjects were all considered primary endpoint failures because of an intra-operative CSF leak following final Valsalva maneuver. Two (2) subjects in the Sutures group received additional treatment to assure durability of closure. For 1 of these subjects, it was subsequently confirmed following database lock that the additional treatment was a rescue treatment rather than for durability.
Safety:
A total of 118 AEs (of which 7 were considered serious) occurred in the EVICEL group and 110 AEs (of which 16 were considered serious) were reported in the Sutures group. The incidence of subjects who experienced at least 1 AE was 84.6% in the EVICEL group and 100.0% in the Sutures group. The most frequent AEs in both treatment groups were vomiting, followed by headache. The incidence of subjects who experienced at least 1 SAE was 19.2% in the EVICEL group and 57.1% in the Sutures group. Overall, the most frequently occurring SAE was pseudomeningocele which occurred in 5/40 subjects (12.5%) followed by hydrocephalus which occurred in 3/40 subjects (7.5%). All SAEs in the EVICEL group were single occurrences.Causality assessment to the product was performed for the EVICEL group only. There were no AEs or serious adverse events (SAEs) considered by the investigator as related or possibly related to EVICEL. The sponsor considered 1 SAE (pseudomeningocele) in the EVICEL group to be possibly related to study product. Because the subject was treated with EVICEL, there could be a possibility that this SAE was due to a lack of expected efficacy of EVICEL, and since the causal relationship of this event to EVICEL could not be excluded, it was considered by the Sponsor’s Study Safety Lead as possibly related to EVICEL.
The incidence of subjects experiencing at least 1 AE considered related or possibly related to the surgical procedure was 80.8% in the EVICEL group and 85.7% in the Sutures group. Overall, most frequently occurring AEs that were considered related or possibly related to surgical procedure were vomiting followed by headache. There were no deaths in either group during the study.
In the EVICEL group, at the 5-day visit, CSF leak status was wound healing impaired, without CSF leak for 3 subjects (11.5%). In the Sutures group, at the 5-day visit, CSF leak status was wound healing impaired, with CSF leak for 1 subject (7.1%) and wound healing impaired, without CSF leak for 2 subjects (14.3%). Pseudomeningocele was experienced by 5/40 subjects (12.5%) overall (EVICEL group 1/26 [3.8%], Sutures group 4/14 [28.6%]) at the 5-day visit. At the 30-day visit, the wound healing assessment was considered normal. There was no CSF leak reported between the 5 day and at 30-day follow up visits for all subjects in either of the treatment groups (100.0%). Pseudomeningocele was experienced by 2 subjects (14.3%) in Sutures group and none of the subjects (0.0%) in the EVICEL group at the 30 day visit.REC name
HSC REC B
REC reference
14/NI/1038
Date of REC Opinion
21 Jul 2014
REC opinion
Favourable Opinion